The endoplasmic reticulum (ER) is a cellular organelle that is responsible for the maturation of proteins and their distribution inside or outside the cell among other things. When it does not work properly, proteins are not well-formed and accumulate interfering some cellular functions. This malfunction, causing what is known as ER stress, has been associated with metabolic diseases such as obesity and type 2 diabetes.
"Until now it was known that ER stress was related to the resistance of neurons in the hypothalamus to the effects of leptin, a hormone that plays a central role on the regulation of hunger in the brain," explains Dr. Claret, lead author of the study. This IDIBAPS team published in 2013 an article in the journal Cell in which the molecular causes relating ER stress in these neurons of the hypothalamus, leptin resistance and obesity, were described. "However, the mechanism linking ER stress in the POMC neurons with alterations in the glucose metabolism remains unknown", he adds.
In this new study published in the journal Cell Reports, researchers have focused on how ER stress in POMC neurons plays a key role in the development of type 2 diabetes in an independent way of obesity. The study was conducted in mice with ER stress in the hypothalamus, caused by genetic modification or by induction with a short-term high fat diet –in order to keep their body weight unaltered. The results show that alpha-MSH processing is altered and is responsible for the overproduction of glucose by the liver, contributing to the characteristic hyperglycemia in diabetes. The mechanism by which this occurs is independent of body weight.
The study also shows that restoring normal levels of alpha-MSH in these mouse models by either administering drugs that relieve ER stress or the neuropeptide directly, glucose levels are restored.
"These results will help to understand the mechanisms involved in the regulation of glucose production in the liver and demonstrate that alterations in the production of alpha-MSH in the hypothalamic POMC neurons contribute to the development of type 2 diabetes," explains Dr. Marc Claret.
Article reference:
Reduced a-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis
Marc Schneeberger, Alicia G. Gómez-Valadés, Jordi Altirriba, David Sebastián, Sara Ramírez, Ainhoa Garcia, Yaiza Esteban, Anne Drougard, Albert Ferrés-Coy, Analía Bortolozzi, Pablo M. Garcia-Roves, John G. Jones, Bruno Manadas, Antonio Zorzano, Ramon Gomis, Marc Claret.
Cell Reports. 9 Jul. DOI: http://dx.doi.org/10.1016/j.celrep.2015.06.041